LAUSR

Simple Summary A point mutation in the Nerve Growth factor gene (leading to the amino acid substitution R100W), causing Hereditary Sensory and Autonomic Neuropathy type V, a condition that primarily affects the sensory nerve cells, whose principal function is to transmit information about sensations, such as pain. Indeed, NGF not only mediates the development and survival of sensory neurons by binding TrkA and p75NTR receptors, but it also plays a role in pain sensation. It is worth noting that the NGF precursor is known to be a biologically active ligand with opposite physiological functions to those of its mature counterpart, and that NGF R100W mutation has been shown to determine an unbalance in the proNGF/NGF levels. Thus, the aim of this work is to elucidate the impact of the R100W mutation on the interactions of p75NTR with the precursor and the mature NGF to unveil the molecular determinants that trigger their different physiological and pathological outcomes. Computer simulations of these complexes allowed us to portray the energetic landscapes and the conformational plasticity, gaining insights into the structural basis of the molecular mechanisms beyond the clinical manifestations of HSAN V patients. Abstract Nerve Growth Factor (NGF), the prototype of the neurotrophin family, stimulates morphological differentiation and regulates neuronal gene expression by binding to TrkA and p75NTR receptors. It plays a critical role in maintaining the function and phenotype of peripheral sensory and sympathetic neurons and in mediating pain transmission and perception during adulthood. A point mutation in the NGFB gene (leading to the amino acid substitution R100W) is responsible for Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), leading to a congenital pain insensitivity with no clear cognitive impairments, but with alterations in the NGF/proNGF balance. The available crystal structures of the p75NTR/NGF and 2p75NTR/proNGF complexes offer a starting point for Molecular Dynamics (MD) simulations in order to capture the impact of the R100W mutation on their binding energetic landscapes and to unveil the molecular determinants that trigger their different physiological and pathological outcomes. The present in silico studies highlight that the stability and the binding energetic fingerprints in the 2p75NTR/proNGF complex is not affected by R100W mutation, which on the contrary, deeply affects the energetic landscape, and thus the stability in the p75NTR/NGF complex. Overall, these findings present insights into the structural basis of the molecular mechanisms beyond the clinical manifestations of HSAN V patients.